CN116635707A - Lab-on-a-chip system with functionalized waveguides - Google Patents

Abstract

A lab-on-a-chip system (100) comprises an optical detection waveguide (122) with an at least partly periodic structure (123, 501, 502, 503, 504), which is configured to couple light (152) from the environment surrounding the optical detection waveguide (122) into the optical detection waveguide (122). The lab-on-a-chip system (100) furthermore comprises a microfluidic network (212), wherein the microfluidic network (212) has a plurality of lines and at least one reaction chamber (211, 211-1, 211-2, 211-3).

Description

Lab-on-a-chip system with functionalized waveguides

Technical Field

Various examples of the invention relate to a compact chip laboratory system having an optical waveguide with an at least partially periodic structure. At least part of the periodic structure may form an in-coupling region for coupling light from a reaction chamber of the microfluidic network into the waveguide; the at least partially periodic structure may also form an out-coupling region for emitting light into the reaction chamber.

Background

The term "lab-on-a-chip (or lab-on-a-chip device)" means a microfluidic network having at least part of the functionality of a macroscopic laboratory on a substrate. Typically, the size of the substrate is relatively small, on the order of a chip card.

A lab-on-a-chip can be used to analyze small amounts (a few picoliters to microliters) of liquid. The sample is transported between the different reaction chambers and the analysis chamber by capillary forces.

Optical detection is usually carried out by light in order to evaluate the process. For example, a microscope may be used to view a reaction chamber of a lab-on-a-chip.

Illuminating and/or detecting microfluidic networks in a lab-on-a-chip using a microscope is both space consuming and expensive.

Disclosure of Invention

There is therefore a need for a lab-on-a-chip system which is realized in a particularly compact manner and which provides integrated optical detection and/or optical excitation in addition to microfluidic networks. Integrated optical targeted detection, that is to say detection with wavelength selectivity and/or with high spatial resolution, is particularly desirable. There is also a need for targeted excitation, that is to say excitation which is well-defined in terms of spatial domain and/or wavelength spectrum.

This object is achieved by the features of the independent patent claims. The features of the dependent patent claims define embodiments.

According to the techniques described herein, a highly compact lab-on-a-chip system may be provided. In addition to classical microfluidic functions provided by microfluidic networks, this may also enable targeted optical excitation and/or targeted optical detection in compact multifunctional elements.

A description of the technology associated with such a multifunctional, high-resolution, high-energy-efficiency simultaneous spectroscopy laboratory chip system with integrated optical detection functionality and/or with integrated optical excitation functionality is given below.

The lab-on-a-chip system includes an optical detection waveguide. The optical detection waveguide has an at least partially periodic structure. This is configured to couple light from the environment surrounding the optical waveguide into the optical waveguide. The lab-on-a-chip system further comprises a microfluidic network. The microfluidic network has a plurality of lines and at least one reaction chamber. The lab-on-a-chip system is configured such that at least one reaction chamber of the microfluidic network can be arranged in the surrounding of the partially periodic structure.

Capillary forces may be used to move liquid in a pipeline of a microfluidic network, for example from a source chamber to at least one reaction chamber. The at least one reaction chamber may be designed to correspond to a cavity in the substrate. The at least one reaction chamber may have one or more feed lines implemented by one or more lines of the microfluidic network. The at least one reaction chamber may further comprise one or more exhaust lines implemented by one or more lines of the microfluidic network. Chemical and/or physical and/or biological processes may occur in at least one reaction chamber. Such a process may then be monitored as part of the optical detection. Alternatively or additionally, such a process may also be powered by photoexcitation. The microfluidic network thus forms a lab-on-a-chip.

Generally, the optical waveguides described herein can include a central region and a cladding region. The light propagates into the central region and is totally reflected at the interface with the cladding region. This is achieved by a suitable choice of materials with different refractive indices. For example, planar or curved waveguides integrated in the substrate can thus be used. As can be seen in fig. 1 to 5, the in-coupled light in the waveguide propagates along the longitudinal surface or longitudinal axis of the light guide. In other words, the propagation direction or propagation surface of the light in the waveguide (e.g. averaged over the length of the waveguide) extends substantially along both interfaces of the waveguide. The propagation surface of the detection waveguide may extend substantially at least partially along and/or parallel to the propagation surface of the illumination waveguide. The propagation surface of the detection waveguide or the illumination waveguide or both may extend substantially at least partially along and/or parallel to the mid-plane/surface of the fluidic system and/or the reaction chamber. The direction of propagation in the detection waveguide may not be along the direction of propagation in the illumination waveguide, e.g. opposite to the direction of propagation in the illumination waveguide.

The at least partially periodic structure of the detection waveguide may form an in-coupling region, as light is coupled into the detection waveguide.

Generally, in various examples described herein, at least a partially periodic structure may be used to functionalize the optical waveguide. Examples of detecting at least partially periodic structures of the waveguide forming the input coupling region are described above. However, it is also conceivable to use at least partly periodic structures, for example in the detection waveguide, for example adjacent to the detector, forming the outcoupling region, or also in the illumination waveguide, for example in order to emit light into at least one reaction chamber, the presence of which is an alternative or in addition to the detection waveguide.

The at least partially periodic structures described herein may be combined with filters. For example, spectral filtering may be performed. The filter parameters may differ depending on the location of the at least partially periodic structure. This makes it possible to achieve extended functionalization. For example, wavelength dependence of imaging optical functions may be achieved. The interference light may be filtered.

Generally, in different examples described herein, at least a portion of the periodic structure may be formed differently. However, different variants may be used equally or in combination to functionalize the waveguide. Table 1 below summarizes some examples of structures that are at least partially periodic.

Table 1: different variants of the partially periodic structure of the in-coupling region and/or the out-coupling region of the optical waveguide can be formed in the different examples described herein. This partly periodic structure makes it possible to provide the required beam shaping and the required imaging properties in a manner that optimizes the installation space. In particular, other optical elements can be saved, which results in a compact design while being light in weight.

Generally, the periodic structure may be strictly periodic. However, one or more design parameters may also vary with position. For example, the filter parameters of the filter layer may vary. Refractive index variations may also be used in the example of an HOE, or cell variations of a grating unit may be used in the example of a DOE. For example, such variations may allow wavelength selective in-coupling or out-coupling of light or imaging optical functions to be achieved in a targeted manner. So that a higher degree of functionalization can be achieved.

In addition, in general, such at least partially periodic structures for functionalizing the optical waveguide may be designed to be partially transparent. Due to the at least partially periodic structure, transparency can be maintained over a large range of angles and wavelengths during normal viewing. In this case, the transparency may depend on the coupling efficiency. As coupling efficiency increases, transparency may also decrease. For the greatest possible transparency, for example, by an at least partially periodic structure, the coupling of radiation in or out of the waveguide may be so efficient that a sufficient number of photons are coupled into or out of the waveguide. At least partially periodic structures-particularly when designed as diffractive structures, see table 1, example I, II, III, IV-can exhibit wavelength selectivity dependent on the angle of incidence, such that these structures have high transparency for large angles and wavelength ranges. In other words, this means that light of different wavelengths can be efficiently coupled into or out of the corresponding optical waveguide depending on the angle of incidence.

In different examples, it is conceivable that the detection waveguide also has an out-coupling region. This may be arranged adjacent to the detector. The out-coupling region may have a specular, prismatic, and/or reflective or transmissive fresnel structure. These variants may be provided as alternatives to or in addition to the partially periodic structure of the outcoupling region.

The output coupling region may be configured to couple light coupled into the detection waveguide from the partially periodic structure of the input coupling region out of the detection waveguide in a detector direction.

The detector may be, for example, a multi-pixel detector. The detector may implement a digital image sensor, such as a CCD sensor or CMOS sensor or SPAD array or silicon photomultiplier. Single photon detection is conceivable. The multi-pixel detector may thus be activated to provide image data.

In this case, the structure implementing at least a partial periodicity of the in-coupling region and the out-coupling region may be configured to generate an image of the at least one reaction chamber on the sensitive surface of the detector.

This means that the at least partly periodic structure is thus configured to transmit light with imaging optical functions here in combination with the outcoupling region.

Different pixels defined by the imaging optical function may then be associated with different wavelengths of light in this case. This may be achieved by: the different pixels are at different distances from the optical axis, so that light emitted by the respective pixels impinges on the at least partially periodic structure at corresponding angles; together with the wavelength selectivity of the coupling efficiency described above, this makes it possible to achieve a situation in which different pixels are associated with different wavelengths. Other variations for generating wavelength selectivity would use different absorbing filters, e.g. attached to different fresnel elements of the fresnel structure, which are then in turn assigned to different pixels.

No other optical imaging element may be arranged between the detector and the out-coupling region. This enables a particularly compact design. Here, focusing on the sensitive surface can be achieved by the imaging optical function of the in-coupling region in combination with the out-coupling region. However, in other variants, at least one optical imaging element may also be arranged. The at least one optical imaging element is used in particular for guiding the portion of the light deflected by the outcoupling region and may be designed, for example, as a lens element. The at least one optical imaging element may be designed, for example, as a lens, a refractive lens or a refractive camera lens.

The structure that enables at least partial periodicity of the input coupling region and the output coupling region may enable infinite-infinite imaging or finite-infinite imaging or infinite-finite imaging or finite-finite imaging.

The at least one reaction chamber may be arranged in a near field of the partial periodic structure with respect to an imaging optical function of the partial periodic structure of the optical detection waveguide. For example, other lens elements or other optically effective elements between the in-coupling region and the reaction chamber are not necessary.

In general, the spatial resolution of the optical imaging function provided by the functionalized detection waveguide may be used to select between different reaction chambers, or alternatively between different locations within a particular reaction chamber. This is explained in more detail below.

The at least one reaction chamber may comprise a plurality of reaction chambers. The at least partially periodic structure and the out-coupling region may then be configured to image pixels of the image corresponding to object points of different ones of the plurality of reaction chambers onto different pixels of the multi-pixel detector. This means that resolution can be achieved by assigning different reaction chambers to different pixels. So that data associated with different reactions or processes in different reaction chambers can be inherently separated by different channels of the multi-pixel detector. This allows for rapid and easy monitoring of multiple reactions or processes in different reaction chambers.

In this context, it is for example conceivable to exploit the wavelength dependence of the imaging optical function in order to examine specific spectral ranges related to reactions or processes in different reaction chambers in a targeted manner. In other words, this means that the allocation of the process to the reaction chambers can be selected in a targeted manner depending on the wavelength measured in connection with the respective reaction chamber. In the example of a DOE or HOE as a partially periodic structure, such wavelength selectivity may be inherently provided by the structure-without providing a spectral filter beyond one or more diffractive structures. For example, when using a tunable light source, for example as explained in more detail below, the wavelength of excitation, i.e. the light source that can be activated to emit light having different wavelengths, can also be set accordingly.

Instead of or in addition to such a separation of the imaging of the different reaction chambers as described above, it is also conceivable to detect the different positions within the reaction chambers in a spatially resolved manner, that is to say to capture images of the reaction chambers in a spatially resolved manner. Thus, the at least partially periodic structure and the out-coupling region may be configured to image pixels of the image corresponding to object points at different locations within the at least one reaction chamber onto different pixels of the multi-pixel detector.

Such spatially resolved images of the reaction chamber can also be used for more complex applications. For example, it is conceivable that the computing unit of the lab-on-a-chip system is configured to count objects of a predefined type in such an image. For example, white blood cells may be counted as part of a blood analysis. Another example pertains to counting malaria parasites per blood volume. This thus enables the implementation of applications requiring spatially resolved images of the reaction chamber in an integrated lab-on-a-chip system without the use of external microscopy devices for imaging.

In different examples, it is conceivable to arrange the optical detection waveguide and the microfluidic network on a common substrate. So that a particularly high degree of integration can be achieved. The lab-on-a-chip system can be provided with particularly small external dimensions.

However, it is also conceivable to arrange the optical detection waveguide and the microfluidic network on different substrates. It is then conceivable to position the two substrates next to each other when performing the measurement. For example, a lab-on-a-chip system may already comprise corresponding guiding elements configured to enable a relative movement of different substrates with respect to each other. For example, the guiding element may be realized by a guide rail. Such an embodiment with two separate substrates may have the advantage that the substrate with the optical element (photonic chip) may be used for excitation and/or measurement together with a plurality of substrates comprising corresponding microfluidic networks (laboratory chips).

As mentioned above, lab-on-a-chip systems are conceivable with an optical illumination waveguide (instead of or in addition to the detection waveguide). The lab-on-a-chip system may also have a light source optically coupled to the illumination waveguide so as to emit light and/or additional light (e.g. for exciting fluorescence) that is then coupled to the detection waveguide. For example, the light sources may be integrated on the corresponding substrate. So that it is possible to provide an on-chip illumination which is thus particularly highly integrated.

In particular, a tunable light source may be used, that is to say a light source configured to emit light of settable wavelength and/or additional light. By selecting a specific wavelength, a specific process in the reaction chamber can be influenced in a targeted manner. The computing unit may be configured to activate the light source accordingly in order to feed light and/or additional light into the illumination waveguide. The computing unit may be further configured to select the settable wavelength of the light and/or the additional light based on a wavelength dependence of the other partially periodic structure and/or an optical imaging function of the partially periodic structure. Thus, if different pixels of, for example, an optical imaging function are assigned to different reaction chambers, for example, one of the reaction chambers can be selected for excitation and/or detection in a targeted manner.

A lab-on-a-chip system according to other aspects includes an optical illumination waveguide. This has an at least partially periodic structure. The structure is configured to couple light from the optical illumination waveguide into an ambient environment of the optical illumination waveguide. The lab-on-a-chip system further comprises a microfluidic network. The microfluidic network has a plurality of lines and at least one reaction chamber. The lab-on-a-chip system is configured such that at least one reaction chamber of the microfluidic network can be arranged in the surrounding of the optical illumination waveguide.

As described above in connection with the optical detection waveguide, the at least partially periodic structure may be configured to transmit light having an imaging optical function, wherein different pixels defined by the imaging optical function are optionally associated with different wavelengths of light. This enables wavelength-resolved illumination, that is to say that a selection can be made between different wavelengths in terms of position and optionally time. Whereby a specific reaction can be stimulated in a targeted manner.

Such a lab-on-a-chip system as described above may be used for various applications. For example, it is conceivable to use such a lab-on-a-chip system for microscopic blood analysis or fluorescence measurement. Even such complex applications, e.g. requiring spatially resolved detection, may be made possible by using functionalized optical waveguides for excitation and/or detection with high integration.

Integrated optical excitation and/or detection combined with external optical excitation and/or detection is conceivable. For this purpose, the lab-on-a-chip system can be used, for example, in combination with a microscope arrangement. According to various examples described herein, the functionalized optical waveguide, in particular the partially periodic structure, may be specifically designed to be at least partially transparent to light of a specific wavelength range. External optical means, such as a microscope means, can then emit additional light to and/or detect said light from at least one reaction chamber in a manner superimposed with the integrated light excitation and/or detection space. Wavelength multiplexing is thus possible. This improves the flexibility of use.

The features set forth above and those described below can be used not only in the corresponding combinations explicitly set forth, but also in other combinations or alone without departing from the scope of the present invention.

Drawings

The above-described features, and advantages of the present invention, as well as the manner of attaining them, will become more apparent and the invention will be better understood by reference to the following description of exemplary embodiments, which are to be construed in greater detail in conjunction with the accompanying drawings.

FIG. 1 is a schematic diagram of a lab-on-a-chip system according to various examples.

Fig. 2 shows a top view of one exemplary implementation of a lab-on-a-chip system according to various examples.

Fig. 3 is a side view of an exemplary implementation of the lab-on-a-chip system of fig. 2.

Fig. 4 is a side view of a variation of the exemplary implementation of the lab-on-a-chip system of fig. 2.

Fig. 5 shows an exemplary implementation of the lab-on-a-chip system of fig. 2 using a microscope arrangement in a side view according to fig. 3.

Fig. 6 is a flow chart of an exemplary method.

Fig. 7 shows an exemplary implementation of an at least partially periodic structure in the form of a diffraction grating according to various examples.

Fig. 8 illustrates one exemplary implementation of an at least partially periodic structure in the form of a volume hologram according to different examples.

Fig. 9 illustrates one exemplary implementation of an at least partially periodic structure in the form of a refractive grating according to various examples.

Fig. 10 illustrates one exemplary implementation of an at least partially periodic structure in the form of a combination of a reflective grating structure and a diffraction grating, according to various examples.

Fig. 11 illustrates a reference implementation of a reflective structure for in-coupling or out-coupling of light.

Fig. 12 schematically illustrates assembly line positioning of a plurality of laboratory chips relative to a photonic chip.

Detailed Description

The invention is explained in more detail below with reference to the drawings, based on preferred embodiments. In the drawings, like reference numerals designate identical or similar elements. The drawings are schematic representations of various embodiments of the invention. Elements illustrated in the figures are not necessarily drawn to scale. Instead, the various elements illustrated in the drawings are presented in a manner that makes their function and general use readily apparent to those skilled in the art. Connections and couplings between the functional units and elements shown in the figures may also be implemented as indirect connections or couplings. The connection or coupling may be implemented in a wired or wireless manner. The functional units may be implemented as hardware, software, or a combination of hardware and software.

Techniques related to lab-on-a-chip systems are described below. The lab-on-a-chip systems described herein use one or more functionalized optical waveguides to provide integrated optical excitation and/or detection. In particular, according to various examples described herein, a functionalized optical waveguide may have an in-coupling region and/or an out-coupling region that implements imaging optical functionality. Spatially resolved measurements can thus also be performed. The imaging optical function may be wavelength selective. The different reaction chambers can also be selectively addressed in a wavelength-resolved manner.

A different effect can be achieved compared to conventional lab-on-a-chip. Some of the effects are listed below. For example, a particularly high degree of integration, that is to say a particularly high level of miniaturization/compactness, can be achieved. Locally targeted photoexcitation is possible; this is not possible, for example, using classical free-propagating optical illumination, for example using a separate microscope device (consistent with the reference implementation). Local targeting detection can also be performed; this is not possible when using classical camera functions or microscope functions consistent with the reference implementation. The potential fluorescence of the substrate caused by excitation can also be eliminated, which is not currently possible due to the indistinguishable excitation/illumination. To this end, the partially periodic structure may be designed such that the partially periodic structure does not forward transmit or image the wavelength range of the substrate fluorescence, but instead reflects or transmits the wavelength range, e.g., while fluorescence from the reaction chamber is forward transmitted or imaged. The "limit of detection" (LOD) may be increased.

Different examples relate to the realization of a lab-on-a-chip by means of a microfluidic network and at least one reaction chamber. In connection with lab-on-a-chip, in particular, space saving should be mentioned as an advantage, since complex processes have to be carried out in a minimum of space. Due to the size of the miniaturized laboratory, the miniaturized laboratory is also easily transportable, which makes it interesting especially in GP surgery and medical emergency outside hospitals.

In general, a lab-on-a-chip thus comprises a microfluidic network and one or more reaction chambers. The liquid may move through the microfluidic network, for example by capillary forces. According to examples described herein, a broad range of biological, chemical and/or physical processes may be performed on LOC-in particular in one or more reaction chambers. The functionality of the microfluidic network may be increased by active components such as micro-valves, pumps and/or sensors integrated into the microfluidic network.

The lab-on-a-chip application is wide. For example, it can be applied to the following fields: medical biology research, chemical analysis or pharmaceutical, biotechnology and modern chemistry. The lab-on-a-chip may be characterized according to different physical characteristics. These physical properties include in particular: a microfluidic type; an excitation method; detection techniques.

Exemplary applications of a lab-on-a-chip that can be implemented by such a process include: microarray analysis and Next Generation Sequencing (NGS). Some applications include the analysis of liquids or biological samples using optical detection and analysis of fluorescent biomolecules. Other applications include blood analysis, malaria detection, fluorescence measurement, cell separation, and the like. In the various examples described herein, all such applications or other applications may be implemented by a lab-on-a-chip. A particular implementation of a lab-on-a-chip or one or more particular applications provided by a lab-on-a-chip is not necessary for the techniques described herein. In other words, the techniques described herein may be combined with a wide variety of implementations of a lab-on-a-chip.

According to various examples, a description is given of an ultra compact, multi-function lab-on-a-chip system. The lab-on-a-chip system comprises a microfluidic network with one or more reaction chambers. The lab-on-a-chip system further comprises one or more multifunctional waveguides for integrated optical excitation and/or integrated optical detection of the sample in the one or more reaction chambers.

For example, lateral input coupling into at least one of the one or more multifunctional waveguides may occur.

According to different examples, a transparent detection function may be made possible, that is to say light from the reaction chamber may be received by at least one waveguide and guided to the detector. This can occur without significant degradation of the microfluidic function.

As can be seen in fig. 1 to 5, light from the one or more reaction chambers, in other words, light emitted from the one or more reaction chambers, is at least partially coupled into the detection waveguide by an at least partially periodic structure. The input coupling causes the light to turn in the propagation direction such that the light propagates in the waveguide along the propagation direction towards the detector. The at least partially periodic structure may be arranged on an end face of the waveguide perpendicular to the propagation direction or on an interface of the waveguide extending in the propagation direction, for example on an interface of the detection waveguide facing the reaction chamber and/or opposite the reaction chamber. The detector may be arranged on the end face in the propagation direction of the light or not, for example at an angle to the propagation direction, for example perpendicular to the propagation direction.

It can also be seen from fig. 1 to 5 that light is coupled out from the illumination waveguide into the surroundings of the illumination waveguide, in which the microfluidic network is arranged, by means of an at least partially periodic structure, such that at least part of the light that is coupled out impinges on the at least one reaction chamber.

According to the different examples described herein, an integrated photo-excitation and/or an integrated optical detection may thus be provided. This means that according to different examples, no external equipment, such as a microscope with an illumination module, has to be used for optical detection and analysis.

However, in some examples, external light excitation and/or detection may be performed in addition to integrated light excitation and/or optical detection in this case. This means that the lab-on-a-chip system as described herein can be used for integrated optical detection, e.g. using an integrated multi-pixel detector, to obtain a corresponding measurement image of at least one reaction chamber; and at the same time other measurement images of the same at least one reaction chamber can be captured using an external microscope device.

This may be achieved by a transparent design of the at least one waveguide-e.g. in a predetermined wavelength range, e.g. in the visible wavelength range-so that wavelength multiplexed measurements may be made using a microscope and an on-chip detector.

The integrated excitation/illumination function based on optical waveguides enables spectrally selective illumination of one or more reaction chambers in space and time. The integrated transparent detection function can realize in-situ detection.

Using the techniques described herein, spectrally selective illumination or excitation of a liquid or biological sample to be analyzed can thus be implemented using an integrated multifunctional illumination waveguide.

Alternatively or additionally, the transparent detection function may also be implemented by using a corresponding optical detection waveguide. This may be integrated into a cover of, for example, a microfluidic network.

Using such techniques, images of one or more reaction chambers may be captured in one detection step in the near field.

The lab-on-a-chip described herein is also particularly useful for detecting low photon fluxes, as is typical of fluorescence from limited amounts of biological samples. The input coupling into the detection waveguide may become particularly efficient.

The lab-on-a-chip system can be integrated on one or more substrates. Such a substrate may be made of the following materials: silicon, plastic and/or glass.

For example, it is conceivable to integrate both one or more optical waveguides (for optical excitation and/or detection) and the microfluidic network on one common substrate.

In a variant, the optical part, that is to say the optical waveguide or waveguides, may be implemented separately from the microfluidic chip, that is to say from the microfluidic network. The lab-on-a-chip system effectively becomes an add-in card interposed between the illumination patch and the imaging patch. Due to the compact illumination and imaging design, the entire system can be implemented in the size of the card reader.

Fig. 1 is a schematic diagram of a lab-on-a-chip system 100. In the illustrated example, the lab-on-a-chip system has two substrates 101, 201, wherein optical elements are provided on the substrate 101 (hereinafter referred to as photonic chip 101) for illumination and detection, and a microfluidic network 212 having one or more reaction chambers 211 is formed on the substrate 201 (hereinafter referred to as laboratory chip 201). In some examples, photonic chip 101 and laboratory chip 201 may also be integrated on a single substrate.

In general, photonic chip 101 and laboratory chip 201 may be arranged in either incident light geometry (see fig. 12) or transmitted light geometry (see fig. 2-5) (the schematic diagram of fig. 1 is not intended to be limiting in this respect). In incident light geometry, non-contact measurements can be made, which can enable rapid measurements on multiple laboratory chips in succession. In incident light geometry, the back side of the laboratory chip 201 can also be designed to be absorptive; this may, for example, enable components of a lab-on-a-chip to be placed there in a flexible manner. In transmitted light geometry, photonic chip 101 can be precisely positioned relative to laboratory chip 201. For this purpose, for example, mechanical guide elements 299 can be provided

In the example of fig. 1, a mechanical guide element 299 is also provided. This mechanical guiding element is configured such that the two substrates 101, 201 can be moved relative to each other. So that the photonic chip 101 can be reused, for example, in combination with a plurality of laboratory chips 201. In general, the mechanical guide element 299 may be used in both incident light geometry and transmitted light geometry.

The stop position, in which the laboratory chip 201 and the photonic chip 101 are positioned to allow optical excitation and/or optical detection of the liquid in the reaction chamber, may be defined by the guide element 299.

Next, details will be described in connection with the photonic chip 101. In the example of fig. 1, this includes detection waveguide 122 and illumination waveguide 112. Generally, photonic chip 101 is contemplated to include detection waveguide 122 or illumination waveguide 112.

The detection waveguide 120 has an at least partially periodic structure 123, which is realized, for example, by a plurality of volume holograms or relief gratings on the surface of the detection waveguide 120. The partially periodic structures 123 may also be bonded by a film. At least part of periodic structure 123 may have refractive and/or reflective beam shaping components; for example, in this case, at least part of periodic structure 123 may implement a fresnel lens. Different examples of implementations of structure 123 with respect to partial periodicity are discussed above in connection with table 1.

In this case, the at least partially periodic structure 123 is configured to couple light 152 from around the detection waveguide 122 into the detection waveguide 122. For example, at least a portion of the periodic structure may be configured to transmit light 152 having imaging optical functionality. In this case, different pixels of the imaging optical function may be associated with different wavelengths of light 152. Depending on the angle of incidence, the coupling efficiency may be selectively high for a particular wavelength (wavelength selectivity). This means that, for example, different processes can be detected in different reaction chambers in a wavelength-resolved manner.

As shown in fig. 1, in the relative positioning of the laboratory chip 201 with respect to the photonic chip 101, one or more reaction chambers 211 are located in these surrounding environments. This means that light 152 from one or more reaction chambers is coupled into the detection waveguide 122. The light 152 then passes through the detection waveguide 122 and is directed to a detector 121, e.g., a multi-pixel detector, via the output coupling structure 124. The detector may be activated by the computing unit 180 to capture an image.

At least part of periodic structure 123 thus forms an input coupling region. At least part of periodic structure 123 and outcoupling region 124 are configured to generate an image of one or more reaction chambers 211 on the sensitive surface of detector 121.

The illumination waveguide 112 is arranged between a light source 111, which may also be activated by the computing unit 180 to emit light 151, and one or more reaction chambers 211. The illumination waveguide 112 comprises an at least partially periodic structure 113-see table 1 for different options. At least a portion of periodic structure 113 is configured to couple light 151 out of illumination waveguide 112 into an ambient environment of illumination waveguide 112 in which one or more reaction chambers 211 are located.

The at least partially periodic structure 113 may in principle be designed to be identical or to correspond to the at least partially periodic structure 123.

Illumination waveguide 112 may also include an in-coupling structure proximate to light source 111 to couple light 151 into illumination waveguide 112 (not shown in fig. 1). The input coupling structure may then be designed as an at least partially periodic structure-see table 1.

At least part of the periodic structure 113, e.g. an in-coupling structure in combination with the illumination waveguide 112, may be configured to transmit light 151 having imaging optical functionality. Different pixels of the imaging optical function may in this case be located at different positions of a particular reaction chamber 211; or also in a different reaction chamber. Different pixels of imaging optical functionality may be associated with different wavelengths of light 151, that is, may provide wavelength selectivity. This means that, for example, different processes can be excited in different reaction chambers in a wavelength-resolved manner.

The example of fig. 1 illustrates light 151 emitted by light source 111 and light 152 detected by detection waveguide 122. For example, light 152 may be generated by fluorescence of a material in one of the reaction chambers 211, which is excited by light 151. In other examples, it is also conceivable to direct the light 151 emitted by the light source 111 from the detection waveguide 122 directly to the detector 121. The corresponding selection may then be made based on the wavelength dependence of the imaging optical function of the partially periodic structures 113, 123. For example, the calculation unit 180 may be configured to activate the light source 111 in a time dependent manner in order to feed the light 151 into the optical illumination waveguide 112, wherein the settable wavelength is selected according to the wavelength dependence of the optical imaging function of the partially periodic structure 113 and optionally of the partially periodic structure 123. The corresponding pixels of the multi-pixel detector 121 assigned to the same wavelength may be read out in a time dependent manner. This therefore means that the calculation unit 180 is able to take into account the wavelength selectivity of the partially periodic structures 113, 123.

Fig. 1 also illustrates that the computing unit 180 is capable of controlling the microfluidic network 212, which is typically optional. For example, a specific micro valve or the like may be controlled. This may occur in a coordinated manner with the activation of the light source 111 and/or the detector 121.

Fig. 1 illustrates that additional light 153 passes through at least a portion of periodic structure 123 and through one or more reaction chambers 211. The additional light 153 may be emitted, for example, by an illumination module of the microscope device and may enter a lens of the microscope device. So that measurements can be made using the detector 121 and at the same time images can be captured using the microscope device. This is possible because the at least partially periodic structure 123 is at least partially transparent to light in the corresponding wavelength range, e.g. to visible light.

Based on a schematic diagram of the lab-on-a-chip system 100, one possible structural implementation is discussed below in connection with fig. 2 and 3. In this case, fig. 2 shows a top view of the lab-on-a-chip system 100, while fig. 3 shows a side view. In this case, the illustrated structural implementation, here transmissive optical geometry, that is to say the microfluidic network 212 is arranged between the waveguides 112, 122, is only an example. It can also be measured in the incident light geometry.

In the illustrated example, the microfluidic network 212 includes a plurality of feed lines 221, 222 (sources not illustrated in fig. 2) to the plurality of reaction chambers 211-1-211-3.

As can be seen from fig. 3, the different reaction chambers 211-1-211-3 can be selectively illuminated (e.g. by activating the light source 111 so as to emit the corresponding light) and the light 152 emitted by the different reaction chambers can be imaged onto different pixels (indicated in fig. 3) of the sensitive surface of the detector 121 by means of the imaging optical functions of the partially periodic structure 113 and the partially periodic structure 123, e.g. in combination with corresponding wavelength dependencies (which wavelength dependencies will mean that the different light beams in fig. 3 indicate the propagation of light having different wavelengths).

Another situation is illustrated in fig. 4. Fig. 4 corresponds in principle to fig. 3, wherein the lab-on-a-chip system 100 shown in fig. 4 comprises a single reaction chamber 211. At least part of periodic structure 123 and out-coupling region 124 are configured to image pixels corresponding to images of object points at different locations within reaction chamber 211 onto different pixels of multi-pixel detector 121.

Fig. 5 in principle corresponds to fig. 3, illustrating how measurements can be performed in parallel with the additional light 153 from the microscope arrangement, due to the partly transparent design of the optical waveguides 112, 122.

Fig. 6 is a flow chart of an exemplary method.

First, in optional block 3005, laboratory chip 201 may be arranged with respect to photonic chip 101. For example, a guiding element 299 may be used for this purpose, for example by inserting the laboratory chip 201 between the two waveguides 112, 122. Thereby forming lab-on-a-chip system 100. Automated arrangements may be made, such as in an assembly line application (see fig. 12).

Block 3005 may be omitted if microfluidic network 212 and one or more waveguides 112, 122 are integrated on a single substrate.

Alternatively, the lab-on-a-chip system 100 can then be fixed on the sample holder of the microscope device in block 3010, see fig. 5.

Measurements may then be performed, as shown in block 3015. To this end, the computing unit 180 may activate both the light source 111 and the detector 121.

This may occur synchronously. For example, depending on the wavelength used by the light source 111, different reaction chambers may be addressed, which corresponds to reading out corresponding pixels of the multi-pixel detector 121. In this case, the wavelength dependence of the imaging optical function of the out-coupling region and the in-coupling region is taken into account. This can be achieved by suitably forming the volume hologram. Another variant is to use a fresnel lens, that is to say with refractive elements in addition to diffractive elements.

At the same time as block 3015, image capture may also be performed using the microscope device in optional block 3020.

In optional block 3025, an evaluation may be performed. For example, the predefined types of objects in the image of the multi-pixel detector as obtained from block 3015 may be counted, e.g. by the calculation unit 180. For example, applications such as blood analysis or malaria detection can thereby be achieved.

Next, different variants of structures for realizing at least a part periodicity according to different examples described herein will be explained in connection with the following figures. In this case, different variants are explained in connection with the detection waveguide 122, so that this realizes an in-coupling region. However, corresponding variations may also be used in connection with another optical waveguide, such as illumination waveguide 112. Corresponding variants can also implement an out-coupling region.

Fig. 7 illustrates aspects related to a partially periodic structure 501 implemented in the form of a diffraction grating structure (see table 1: example I, example IV). In this case, the diffraction grating structure 501-DOE-is integrated on the top side 122-1 of the detection waveguide 122, i.e. in the form of a surface relief (e.g. produced by laser scribing, thermally induced material removal, or produced by a stamping method). Using the diffraction grating structure 601 in the example of fig. 7, light can be coupled in via the bottom side 122-2. Alternatively or additionally, the diffraction grating structure 501 may also be arranged on the bottom side 122-2, that is to say facing the reaction chamber.

For example, the side of the diffraction grating structure 501 facing away from the detection waveguide 122 may be coated with a reflective or absorptive material. So that the inherent wavelength selectivity of the diffraction grating structure 501 can be modified.

The thickness of the diffraction grating structure 501 is small compared to the thickness of the detection waveguide 122. So that high integration can be achieved.

Fig. 8 illustrates aspects related to a partially periodic structure 502, here implemented in the form of a diffraction volume hologram (see table 1, example II). The diffractive beam shaping effect can be achieved by modulating the refractive index. The volume hologram 502 is embedded in the detection waveguide 122. Multiple volume holograms can also be used adjacently (multiplexed).

Fig. 9 illustrates aspects related to a partially periodic structure 503, here implemented in the form of a diffractive fresnel structure (see table 1, example V). As can be seen from comparing fig. 7 and 9, the refractive periodic structure 503 has a larger periodicity, and the thickness of the structure perpendicular to the width of the detection waveguide 122 is larger than the corresponding parameters of the grating structure 501. In particular, the thickness of the refractive grating structure 503 is not small compared to the thickness of the detection waveguide 122.

For example, a typical thickness of DOE 501 in fig. 7 is in the range of 0.5 μm to 10 μm; and the typical thickness of the refractive structure 503 of fig. 9 is in the range of 80 μm or more.

The different fresnel elements of the fresnel structure may each have a curved surface (not shown in fig. 9) to create a refractive imaging effect.

The periodicity of the reflective periodic structure 503 may correspond to the spatial resolution of the imaging optical function. This means that each fresnel unit can obtain a corresponding pixel. This means, therefore, that different fresnel units of the fresnel structure can be assigned to different reaction chambers to be imaged by different pixels, for example (see fig. 3). In contrast, the cells of many of the grating elements of the diffraction grating structure 501 of fig. 7 may interact in a phase coherent manner (by constructive or destructive interference) to define the location points of the corresponding imaging optical function.

One or more filter layers may be applied to the fresnel structure 503. For example, different "prismatic" elements of the fresnel structure 503 may be coated with different filters, that is, filters that absorb different wavelengths, for example. Thereby a wavelength dependence of the light in-coupling, in particular a different wavelength dependence of different location points, e.g. of the imaging function, can be achieved.

Fig. 10 illustrates aspects related to a partially periodic structure 504 implemented herein in the form of a diffraction-reflection combined structure (see table 1, example III). In the example of FIG. 10, the grating structure is disposed on the bottom side 122-2 of the detection waveguide 122 and the Fresnel structure is disposed on the top side 122-1. The grating structure and the fresnel structure may also be integrated together on the same side. For example, aberrations in the fresnel structure can be reduced or compensated for by the diffractive structure.

Fig. 11 illustrates aspects related to non-periodic structures for reference. Compared to the variants of the at least partially periodic structures in fig. 7 to 10, the non-periodic structures are thicker, thus preventing a high level of integration of the in-coupling region.

Fig. 12 illustrates aspects related to one possible implementation of the lab-on-a-chip system 100. In the example of fig. 12, the laboratory chip 201 and the photonic chip 101 are not arranged in a "sandwich structure" according to the examples of fig. 2 to 5, but are arranged laterally to each other. This corresponds to "reflected light geometry", in contrast to "transmitted light geometry" according to fig. 2 to 5. This means that measurements can be made in reflection; this means that light emitted from the illumination waveguide is reflected into the one or more reaction chambers 211 and then collected by the detection waveguide reflection.

This reflected light geometry has certain advantages. For example, there may be no need to establish mechanical intervention between the laboratory chip 201 and the photonic chip 101 via the guiding element 299. The guide element may be omitted. Multiple laboratory chips 201, 201-1, 201-2 may be placed in a measurement position (indicated by horizontal arrows in fig. 12) relative to photonic chip 101 in a serial automated process, for example using a conveyor belt or "pick and place" machine. Optical coupling occurs only through the interface, which makes relative positioning easier. High throughput of different measurements can be achieved.

In summary, a description has been given above of techniques that enable a particularly high level of integration of lab-on-a-chip systems. In particular, optical detection and/or optical illumination or excitation may be highly integrated. This may be made possible by using one or more at least partially periodic optical structures that enable the functionalization of the illumination waveguide and/or the detection waveguide. Classical individual lens elements or individual prisms, which would normally occupy a relatively large amount of space, can thereby be dispensed with. At the same time, efficient in-coupling and/or out-coupling of light into and/or out of the respective waveguides may be achieved by a suitable design of the at least partly periodic optical structure. Such efficient in-coupling and/or out-coupling may be supplemented with other functionalities, such as tailored wavelength dependence adapted to the microfluidic laboratory to be examined. In addition, images from different points within the reaction chamber may also be used to implement complex counting applications. Interference light, for example, interference light caused by fluorescence of the substrate, may be filtered. A description is also given above of different structural implementations of a lab-on-a-chip system suitable for different application cases (e.g. individual tests or quality tests), wherein the decoupling of optics and microfluidics can here be adapted to the corresponding application case by means of a suitable mechanical configuration (guiding elements, incident light geometry and transmitted light geometry).

It goes without saying that the features of the embodiments and aspects of the invention described above can be combined with one another. In particular, these features may be used not only in the described combinations, but also in other combinations or alone, without departing from the scope of the invention.

For example, a description has been given above of different implementations of a lab-on-a-chip system with a detection waveguide having a partially periodic structure for the in-coupling of light. A lab-on-a-chip system with only an illumination waveguide having a suitably configured partially periodic structure may also be used. For example, if illumination and detection are performed at different times, the same light wave can also be used for both illumination and detection, that is to say for the same at least partially periodic structure once for light out-coupling and once for light in-coupling. The beam splitter may then be used to direct the detected light to a detector and to receive light to be emitted from the light source.

Claims (19)

1. A lab-on-a-chip system (100), comprising:

-an optical detection waveguide (122) having an at least partly periodic structure (123, 501, 502, 503, 504), the optical detection waveguide being configured to couple light (152) from the environment surrounding the optical detection waveguide (122) into the optical detection waveguide (122), and

A microfluidic network (212), wherein the microfluidic network (212) has a plurality of lines and at least one reaction chamber (211, 211-1, 211-2, 211-3),

wherein the lab-on-a-chip system (100) is configured such that at least one reaction chamber (211, 211-1, 211-2, 211-3) of the microfluidic network (212) can be arranged in the surroundings of the optical detection waveguide (122).

2. The lab-on-a-chip system (100) of claim 1, further comprising:

a multi-pixel detector (121) having a sensitive surface,

wherein the optical detection waveguide (122) has an output coupling region (124) arranged adjacent to the multi-pixel detector (121) and configured to couple the light (152) out of the optical detection waveguide (122) in the direction of the multi-pixel detector (121),

wherein the at least partially periodic structure (123, 501, 502, 503, 504) and the outcoupling region (124) are configured to generate an image of the at least one reaction chamber (211, 211-1, 211-2, 211-3) on the sensitive surface.

3. The lab-on-a-chip system (100) of claim 2,

wherein the at least one reaction chamber (211, 211-1, 211-2, 211-3) comprises a plurality of reaction chambers (211, 211-1, 211-2, 211-3),

Wherein the at least partially periodic structure (123, 501, 502, 503, 504) and the output coupling region (124) are configured to image pixels of the image corresponding to object points in different ones (211, 211-1, 211-2, 211-3) of the plurality of reaction chambers (211, 211-1, 211-2, 211-3) onto different pixels of the multi-pixel detector (121).

4. The lab-on-a-chip system (100) of claim 2 or 3,

wherein the at least partially periodic structure (123, 501, 502, 503, 504) and the output coupling region (124) are configured to image pixels of the image corresponding to object points at different positions in one of the at least one reaction chamber (211, 211-1, 211-2, 211-3) onto different pixels of the multi-pixel detector (121).

5. The lab-on-a-chip system (100) of claim 4, further comprising:

-a calculation unit (180) configured to count objects of a predefined type in an image of the multi-pixel detector (121).

6. The lab-on-a-chip system (100) of one of the preceding claims,

wherein the optical detection waveguide (122) and the microfluidic network (212) are disposed on a common substrate.

7. The lab-on-a-chip system (100) of one of claims 1-5,

wherein the optical detection waveguide (122) and the microfluidic network (212) are arranged on different substrates (101, 201),

wherein the lab-on-a-chip system (100) optionally further comprises:

-a guiding element (299) configured to enable relative movement of the different substrates (101, 201) with respect to each other.

8. The lab-on-a-chip system (100) of one of the preceding claims,

wherein the at least partially periodic structure (123, 501, 502, 503, 504) is configured to transmit light (152) having imaging optical functionality,

wherein different pixels defined by the imaging optical function are associated with different wavelengths of the light (152).

9. The lab-on-a-chip system (100) of one of the preceding claims, further comprising:

-an optical illumination waveguide (112) comprising further at least partially periodic structures (113, 501, 502, 503, 504) configured to emit the light (152) or additional light (151) into the reaction chamber (211, 211-1, 211-2, 211-3).

10. The lab-on-a-chip system (100) of claim 9, further comprising:

-a light source (111) optically coupled to the optical illumination waveguide (112) and configured to emit wavelength settable light (151) and/or additional light (152), and

A calculation unit (180) configured to activate the light source for feeding the light (151) and/or the additional light (152) into the optical illumination waveguide (112),

wherein the computing unit (180) is further configured to select the settable wavelength of the light (151) and/or the additional light (152) based on a wavelength dependence of an optical imaging function of the at least partially periodic structure and/or of the other at least partially periodic structure.

11. The lab-on-a-chip system (100) of one of the claims 1-10,

wherein the at least partially periodic structure (123, 502) is realized by a holographic optical element HOE, optionally comprising one or more volume holograms integrated into the detection waveguide (122) or holograms applied to the detection waveguide (122).

12. The lab-on-a-chip system (100) of one of the claims 1-10,

wherein the at least partially periodic structures (123, 503, 504) shape the light (152) by refraction and/or reflection.

13. The lab-on-a-chip system (100) of one of the claims 1-10,

wherein the at least partially periodic structure (123, 503, 504) shapes the light (152) by diffraction as a diffractive optical element DOE.

14. The lab-on-a-chip system (100) of one of the preceding claims,

wherein the at least partially periodic structure (123, 501, 502, 503, 504) is at least partially transparent to visible light (153).

15. The lab-on-a-chip system (100) of one of the preceding claims,

wherein the at least partially periodic structure (123, 501, 502, 503, 504) is configured to couple the light (152) into the optical detection waveguide (122) having wavelength dependence,

wherein the at least one reaction chamber is integrated on the substrate,

wherein the wavelength dependence does not allow for coupling of additional light generated by fluorescence of the substrate into the optical detection waveguide (122) or allows for such coupling only in the presence of suppression.

16. A method, comprising:

-using the lab-on-a-chip system (100) of one of the preceding claims to obtain a measurement image based on light coupled into the optical detection waveguide (122), and

-obtaining further measurement images of the at least one reaction chamber (211, 211-1, 211-2, 211-3) using a microscope device while capturing the measurement images.

17. A lab-on-a-chip system (100), comprising:

-an optical illumination waveguide (112) having an at least partly periodic structure (113, 501, 502, 503, 504), the optical illumination waveguide being configured to couple light from the optical illumination waveguide (112) into an ambient environment of the optical illumination waveguide (112), and

A microfluidic network (212), wherein the microfluidic network (212) has a plurality of lines and at least one reaction chamber (211, 211-1, 211-2, 211-3),

wherein the lab-on-a-chip system (100) is configured such that at least one reaction chamber (211, 211-1, 211-2, 211-3) of the microfluidic network (212) can be arranged in the surroundings of the optical illumination waveguide (112).

18. The lab-on-a-chip system (100) of claim 17, wherein the at least partially periodic structure is configured to emit at least part of the outcoupled light to the at least one reaction chamber.

19. Use of the lab-on-a-chip system (100) of claims 1 to 15 or 17 or 18 for microscopic blood analysis or fluorescence measurement.